11-78079609-G-T

Position:

• chr11-78079609-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004549.6(NDUFC2):​c.136C>A​(p.Leu46Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L46V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NDUFC2 NM_004549.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0690

Genes affected

NDUFC2 (HGNC:7706): (NADH:ubiquinone oxidoreductase subunit C2) Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrion. Part of mitochondrial respiratory chain complex I. Implicated in nuclear type mitochondrial complex I deficiency. [provided by Alliance of Genome Resources, Apr 2022]

NDUFC2-KCTD14 (HGNC:42956): (NDUFC2-KCTD14 readthrough) This locus represents naturally occurring read-through transcription between the neighboring NDUFC2 (NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2, 14.5kDa) and KCTD14 (potassium channel tetramerisation domain containing 14) genes on chromosome 11. The read-through transcripts share sequence identity with the upstream gene product and one variant has a frameshifted C-terminal region derived from the downstream gene exons. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079265594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFC2	NM_004549.6	c.136C>A	p.Leu46Ile	missense_variant	1/3	ENST00000281031.5	NP_004540.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFC2	ENST00000281031.5	c.136C>A	p.Leu46Ile	missense_variant	1/3	1	NM_004549.6	ENSP00000281031.4
NDUFC2-KCTD14	ENST00000612612.5	c.136C>A	p.Leu46Ile	missense_variant	1/4	2		ENSP00000478766.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1409690 Hom.: 0 Cov.: 66 AF XY: 0.00 AC XY: 0 AN XY: 696450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.57
DEOGEN2	Benign	0.016	T;T;.;.;T;.;T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.51	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.079	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	.;L;.;.;.;.;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.52	N;N;.;.;N;N;N;N;N
REVEL	Benign	0.029
Sift	Benign	0.34	T;T;.;.;T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T;T;T;T;T
Polyphen		0.10	.;.;.;.;B;.;.;.;.
Vest4		0.15
MutPred		0.25		Loss of catalytic residue at L46 (P = 0.0599);Loss of catalytic residue at L46 (P = 0.0599);Loss of catalytic residue at L46 (P = 0.0599);Loss of catalytic residue at L46 (P = 0.0599);Loss of catalytic residue at L46 (P = 0.0599);Loss of catalytic residue at L46 (P = 0.0599);Loss of catalytic residue at L46 (P = 0.0599);Loss of catalytic residue at L46 (P = 0.0599);Loss of catalytic residue at L46 (P = 0.0599);
MVP		0.085
MPC		0.68, 0.69
ClinPred		0.080	T
GERP RS		-0.89
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.16
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs8875; hg19: chr11-77790655;